RESUMEN
BACKGROUND: Sirtuin 1 (SIRT1) is a NAD+ sensitive deacetylase that has been linked to longevity and has been suggested to confer beneficial effects that counter aging-associated deterioration. Muscle repair is dependent upon satellite cell function, which is reported to be reduced with aging; however, it is not known if this is linked to an aging-suppression of SIRT1. This study tested the hypothesis that Sirtuin 1 (SIRT1) overexpression would increase the extent of muscle repair and muscle function in older mice. METHODS: We examined satellite cell dependent repair in tibialis anterior, gastrocnemius, and soleus muscles of 13 young wild-type mice (20-30 weeks) and 49 older (80+ weeks) mice that were controls (n = 13), overexpressed SIRT1 in skeletal muscle (n = 14), and had a skeletal muscle SIRT1 knockout (n = 12) or a satellite cell SIRT1 knockout (n = 10). Acute muscle injury was induced by injection of cardiotoxin (CTX), and phosphate-buffered saline was used as a vector control. Plantarflexor muscle force and fatigue were evaluated before or 21 days after CTX injection. Satellite cell proliferation and mitochondrial function were also evaluated in undamaged muscles. RESULTS: Maximal muscle force was significantly lower in control muscles of older satellite cell knockout SIRT1 mice compared to young adult wild-type (YWT) mice (P < 0.001). Mean contraction force at 40 Hz stimulation was significantly greater after recovery from CTX injury in older mice that overexpressed muscle SIRT1 than age-matched SIRT1 knockout mice (P < 0.05). SIRT1 muscle knockout models (P < 0.05) had greater levels of p53 (P < 0.05 MKO, P < 0.001 OE) in CTX-damaged tissues as compared to YWT CTX mice. SIRT1 overexpression with co-expression of p53 was associated with increased fatigue resistance and increased force potentiation during repeated contractions as compared to wild-type or SIRT1 knockout models (P < 0.001). Muscle structure and mitochondrial function were not different between the groups, but proliferation of satellite cells was significantly greater in older mice with SIRT1 muscle knockout (P < 0.05), but not older SIRT1 satellite cell knockout models, in vitro, although this effect was attenuated in vivo after 21 days of recovery. CONCLUSIONS: The data suggest skeletal muscle structure, function, and recovery after CTX-induced injury are not significantly influenced by gain or loss of SIRT1 abundance alone in skeletal muscle; however, muscle function is impaired by ablation of SIRT1 in satellite cells. SIRT1 appears to interact with p53 to improve muscle fatigue resistance after repair from muscle injury.